US20240228638A1 - Method for Treating Chronic Obstructive Pulmonary Disease With an ST2 Antagonist - Google Patents

Method for Treating Chronic Obstructive Pulmonary Disease With an ST2 Antagonist Download PDF

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US20240228638A1
US20240228638A1 US18/528,122 US202318528122A US2024228638A1 US 20240228638 A1 US20240228638 A1 US 20240228638A1 US 202318528122 A US202318528122 A US 202318528122A US 2024228638 A1 US2024228638 A1 US 2024228638A1
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amino acid
acid sequence
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Michele Anne GRIMBALDESTON
Divya Mohan
Ahmed Yousuf
Christopher Brightling
Dorothy Sze-Wing Cheung
David Fong Choy
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Genentech Inc
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Genentech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present application contains a Sequence Listing that has been submitted electronically in XML format. Said XML copy, created on Nov. 27, 2023, is named “01146-0108-04US_ST26.xml” and is 39,852 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.
  • ST2 is a binding receptor for interleukin-33 (IL-33), a cytokine related to IL-1 and IL-18 and also known as NF-HEV or IL-1F11.
  • ST2 is expressed as both a soluble non-signaling variant (soluble ST2 or sST2) and a full-length membrane-spanning form (FL ST2, ST2 or ST2L) that mediates cellular responses to IL-33.
  • soluble ST2 or sST2 soluble non-signaling variant
  • FL ST2, ST2 or ST2L full-length membrane-spanning form
  • lymphocytes particularly IL-5 and IL-13-expressing T helper cells, natural killer (NK) and natural killer-T (NKT) cells, as well as many so-called innate immune cells, such as mast cells, basophils, eosinophils, macrophages and type 2 innate lymphoid cells (ILC2) (Neill, Wong et al. 2010).
  • IL-33 binding to ST2 on these cells leads to the recruitment of a broadly-expressed co-receptor known as the IL-1R Accessory Protein (AcP) and the activation of pro-inflammatory signaling, similar to IL-1 and IL-18.
  • IL-33 is thus able to directly activate ST2-expressing cells or enhance their activation when in the presence of other activating stimuli.
  • IL-33-induced cellular responses include the production of inflammatory cytokines, such as IL-5, IL-6, IL-13, TNF, IFN- ⁇ and GM-CSF as well as the production of chemokines, such as CXCL8, CCL17 and CCL24.
  • IL-33 has also been shown to enhance acute allergic responses by augmenting mast cell and basophil activation triggered by IgE receptor signaling or other mast cell and basophil activators.
  • IL-33 will also enhance the recruitment, survival and adhesive properties of ST2 expressing immune cells and thus is important in provoking and sustaining cellular inflammation in local tissues.
  • IL-33 The pro-inflammatory actions of IL-33 on innate and adaptive immune cells culminate to promote a number of pathologic processes. In the lungs, these include increased airway inflammation, mucus production, airway hyper responsiveness and fibrotic remodeling. IL-33 can also contribute to localized inflammation in the joints as well as cutaneous and articular hypernociception, by promoting the production of proinflammatory cytokines (Verri, Guerrero et al. 2008; Xu, Jiang et al. 2008). Excessive IL-33 has been linked to pathologic collagen deposition and fibrosis and also contributes to epithelial damage in the setting of inflammatory bowel disease.
  • COPD chronic obstructive pulmonary disease
  • GOLD Global Initiative for Chronic Obstructive Lung Disease
  • FEV1 forced expiratory volume in 1 second
  • FVC forced vital capacity
  • COPD exacerbation defined as an acute worsening of respiratory symptoms that result in additional therapy (GOLD 2021). While there exists some variability in the definition of exacerbation severity, severity is often classified as mild (increase in respiratory symptoms controllable by an increase of usual medication), moderate (requiring treatment with systemic corticosteroids and/or antibiotics), or severe (requiring hospitalization) (Solem et al., 2013, GOLD 2021). An increasing rate of COPD exacerbations is associated with decline in lung function, reduced quality of life, and death (Miravitlles et al. 2004. Halpin et al. 2012). Although the frequency of exacerbations increases with the severity of disease (Halpin et al.
  • exacerbations affect individuals even with moderate COPD.
  • Prior history of exacerbation, rather than airflow limitation, is the single best predictor for increased risk of future exacerbations (Hurst et al. 2010).
  • COPD exacerbations are not only a major cause of morbidity and mortality, but also account for the greatest proportion of the total COPD healthcare costs (AbuDagga et al. 2013, Solem et al. 2013).
  • Embodiment 1 A method of treating chronic obstructive pulmonary disease (COPD) in a patient comprising administering 476 mg of an ST2 antagonist to the patient on Day 1 of a treatment period.
  • COPD chronic obstructive pulmonary disease
  • Embodiment 2 A method of reducing the frequency of moderate to severe exacerbations in a patient having COPD comprising administering 476 mg of an ST2 antagonist to the patient on Day 1 of a treatment period.
  • Embodiment 3 A method of reducing the frequency of moderate to severe exacerbations in a patient having COPD comprising administering an effective amount of an ST2 antagonist to achieve a clinical improvement of at least 10%, at least 20%, at least 21%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40% or at least 45% annualized exacerbation rate reduction than standard of care (SOC).
  • SOC standard of care
  • Embodiment 4 A method of reducing the frequency of moderate to severe exacerbations in a patient having COPD comprising administering an ST2 antagonist to the patient in an amount effective to achieve a greater clinical improvement in the number of exacerbations than standard of care (SOC), said patient having a baseline blood eosinophil count ⁇ 300 eosinophils/ ⁇ L.
  • SOC standard of care
  • Embodiment 7 A method of reducing the frequency of moderate to severe exacerbations in a patient having COPD comprising administering an ST2 antagonist to the patient in an amount effective to achieve a greater clinical improvement in the number of exacerbations than SOC, said patient having a modified Medical Research Council (mMRC) dyspnea scale score ⁇ 2 and a COPD assessment test score (CAT) of ⁇ 10.
  • mMRC Medical Research Council
  • CAT COPD assessment test score
  • Embodiment 10 A method of improving baseline blood eosinophil count in a patient having COPD comprising administering an ST2 antagonist to the patient in an amount effective to reduce mean blood eosinophil count by at least about 25%, e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45% compared to baseline, after about 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks following administration of a first dose of an ST2 antagonist.
  • Embodiment 13 A method for maintaining and/or improving lung function in a patient having COPD comprising administering an ST2 antagonist to the patient in an amount effective to achieve a greater clinical improvement in lung function than SOC, wherein clinical improvement is demonstrated by a mean difference compared to baseline of at least about 5% as measured by post-BD FEV1 at 4 weeks, 12 weeks, 24 weeks, 36 weeks, or 48 weeks from the start of treatment.
  • Embodiment 29 The method of any one of the preceding embodiments, comprising administering the ST2 antagonist every 2 weeks.
  • Embodiment 39 The method of any one of the preceding embodiments, wherein the patient has post-bronchodilator FEV1/FVC ⁇ 0.7.
  • Embodiment 52 The method of any one of the preceding embodiments, which improves at least one non-E-RS COPD domain from baseline at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment.
  • Embodiment 55 The method of any one of the preceding embodiments, which improves the proportion of patients with symptom improvement, defined as decrease from baseline of ⁇ 2 points from baseline in E-RS:COPD total score, at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment.
  • Embodiment 62 The method of any one of the preceding embodiments, which improves the duration of hospital stay for severe COPD exacerbations.
  • Embodiment 63 The method of any one of the preceding embodiments, which reduces healthcare utilization for severe COPD exacerbations.
  • Embodiment 67 The method of any one of the preceding embodiments, which improves the absolute change from baseline in time in moderate and vigorous physical activity at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment.
  • Embodiment 69 The method of any one of the preceding embodiments, which improves the annualized rate of moderate and severe COPD exacerbations over a blinded treatment period.
  • Embodiment 70 The method of any one of the preceding embodiments, which improves health-related quality of life as measured by patient reported outcome (PRO) as compared to SOC.
  • PRO patient reported outcome
  • Embodiment 74 The method of any one of the preceding embodiments, which improves the absolute change from baseline in rescue inhaler use at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment.
  • Embodiment 75 The method of any one of the preceding embodiments, which improves the absolute change from baseline in nightly total sleep time at 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 50 weeks, or 52 weeks from the start of treatment.
  • Embodiment 76 The method of any one of the preceding embodiments, wherein the ST2 antagonist is administered to the patient in combination with SOC.
  • Embodiment 77 The method of any one of the preceding embodiments, wherein the ST2 antagonist is administered to the patient in combination with inhaled corticosteroids (ICS).
  • ICS corticosteroids
  • Embodiment 79 The method of any one of the preceding embodiments, wherein the ST2 antagonist is administered to the patient in combination with ICS plus long-acting betaagonist (LABA).
  • CLA long-acting betaagonist
  • Embodiment 86 The method of any one of the preceding embodiments, wherein the patient is a former smoker.
  • Embodiment 102 The method of any one of embodiments 92 to 101, wherein the anti-ST2 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • Embodiment 105 An ST2 antagonist for use in a method of reducing the frequency of moderate to severe exacerbations in a patient having COPD comprising administering 476 mg of an ST2 antagonist to the patient on Day 1 of a treatment period.
  • Embodiment 117 An ST2 antagonist for use in a method of treating chronic obstructive pulmonary disease (COPD) in a patient comprising administering an effective amount of an ST2 antagonist to the patient, wherein the patient is selected for treatment on the basis of level of sST2 in a sample derived from the patient is determined to be at or above a reference level of sST2.
  • COPD chronic obstructive pulmonary disease
  • Embodiment 121 An ST2 antagonist for use in a method of treating COPD in a patient comprising administering an effective amount of an ST2 antagonist to the patient, wherein the patient is selected for treatment on the basis of the level of one or more biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein) and single nucleotide polymorphisms (SNPs) of genes related to COPD (e.g., IL1RL1, IL33) in a sample derived from the patient.
  • biomarkers selected from eosinophils, IL-33 pathway markers, inflammatory proteins (e.g., fibrinogen, C-reactive protein) and single nucleotide polymorphisms (SNPs) of genes related to COPD (e.g., IL1RL1, IL33) in a sample derived from the patient.
  • Embodiment 125 The ST2 antagonist of any one of embodiments 106 to 124, wherein the use comprises administering 476 mg of the ST2 antagonist to the patient on Day 1 of a treatment period.
  • Embodiment 127 The ST2 antagonist of any one of embodiments 104 to 125, wherein the use comprises administering the ST2 antagonist every 2 weeks.
  • Embodiment 129 The ST2 antagonist of any one of embodiments 104 to 125, wherein the use comprises administering 476 mg of the ST2 antagonist every 2 weeks.
  • Embodiment 131 The ST2 antagonist of any one of embodiments 106 to 124, wherein the use comprises administering 490 mg of the ST2 antagonist every 4 weeks.
  • Embodiment 132 The ST2 antagonist of any one of embodiments 106 to 124, wherein the use comprises administering 490 mg of the ST2 antagonist every 2 weeks.
  • Embodiment 133 The ST2 antagonist of any one of embodiments 104 to 132, wherein the ST2 antagonist is an inhibitor of ST2 biological activity.
  • Embodiment 134 The ST2 antagonist of any one of embodiments 102 to 133, wherein the ST2 antagonist binds to human ST2 or to human IL-33.
  • Embodiment 135. The ST2 antagonist of any one of embodiments 102 to 134, wherein the ST2 antagonist is an anti-ST2 antibody.
  • Embodiment 136 The ST2 antagonist of embodiment 135, wherein the anti-ST2 antibody is a human antibody.
  • Embodiment 137 The anti-ST2 antibody of embodiment 135 or embodiment 136, wherein the anti-ST2 antibody comprises:
  • Embodiment 138 The anti-ST2 antibody of embodiment 135 or embodiment 136, wherein the anti-ST2 antibody comprises:
  • Embodiment 139 The anti-ST2 antibody of embodiment 135 or embodiment 136, wherein the anti-ST2 antibody comprises (a) heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, H-CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 31, H-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, light chain complementarity determining region (L-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, L-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and L-CDR3 comprising the amino acid sequence of SEQ ID NO: 6; or (b) heavy chain complementarity determining region (H-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 35, H-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, H-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, light chain complementarity determining region (L-CDR
  • Embodiment 140 The anti-ST2 antibody of any one of embodiments 135 to 139, wherein the anti-ST2 antibody comprises:
  • Embodiment 143 The anti-ST2 antibody of any one of embodiments 135 to 142, wherein the anti-ST2 antibody comprises:
  • Embodiment 144 The anti-ST2 antibody of any one of embodiments 135 to 143, wherein the anti-ST2 antibody comprises:
  • Embodiment 145 The anti-ST2 antibody of any one of embodiments 135 to 144, wherein the anti-ST2 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • FIG. 1 shows the distribution of the number of moderate-to-severe exacerbations among subjects by placebo and anti-ST2 treatment arms.
  • FIG. 2 shows the annualized exacerbation rate for all-comers for placebo or anti-ST2 treatment arm. For all-comers, the reduction in annualized rate of moderate/severe COPD exacerbations was 22% in those receiving astegolimab versus placebo.
  • FIG. 5 A- 5 B show the SGRQ-C total scores based on the baseline blood eosinophil sub-groups for placebo and anti-ST2 treatment arms.
  • FIG. 6 shows the change from baseline in post-bronchodilator forced expiratory volume (post-BD FEV1) during the 48 weeks for all-comers for placebo and astegolimab treatment arms. Astegolimab treatment demonstrated a trend in improvement of FEV1.
  • FIG. 7 A- 7 B show the baseline blood eosinophil sub-group analysis for post-BD FEV1 for placebo and anti-ST2 treatment ams.
  • FIG. 8 A- 8 B show the change from baseline in blood eosinophil level over 48 weeks for placebo and anti-ST2 treatment arms.
  • FIG. 10 A- 10 C show frequency ( FIG. 10 A ) or number per patient ( FIG. 10 B- 10 C ) of certain adverse events, including serious adverse events, for treatment compared to placebo.
  • FIG. 11 Treatment effect (percent rate reduction, top) and annualized exacerbation rate per treatment arm (bottom) are plotted and faceted by IL1RL1 TIR domain tag SNP (rs10206753) genotype.
  • FIG. 12 ZENYATTA treatment effect (percent rate reduction, top) and annualized exacerbation rate per treatment arm (bottom) are plotted and faceted by pre-treatment categories of serum sST2 levels ( ⁇ or ⁇ median).
  • FIG. 13 ST2OP treatment effect (percent rate reduction, top) and annualized exacerbation rate per treatment arm (bottom) are plotted and faceted by pre-treatment categories of serum sST2 levels ( ⁇ or ⁇ median).
  • FIG. 15 ST2OP treatment effect (percent rate reduction, top) and annualized exacerbation rate per treatment arm (bottom) are plotted and faceted by pre-treatment categories of baseline lung ⁇ -diversity ( ⁇ or ⁇ median).
  • ST2 is expressed on inflammatory cells including mast cells, basophils, innate lymphoid cells, T lymphocytes, and macrophages.
  • IL33 is expressed at high levels in epithelial cells of mucosal tissues, particularly the lung, and acts as an ‘alarmin,’ being released upon inflammatory cell death, infection, or injury, to initiate innate immune responses.
  • IL33 activity is elevated in multiple human respiratory diseases including asthma, COPD, IPF, and ARDS.
  • Preclinical studies have shown that therapeutic IL33 inhibition is protective in pulmonary ARDS models, and ST2- or IL33-deficient mice exposed to cigarette smoke have decreased inflammatory responses in response to subsequent respiratory viral infections without compromising antiviral host defense.
  • a Phase II study has been designed to investigate the effect of anti-ST2 antibody on chronic obstructive pulmonary disease.
  • the study is a randomized, double-blind, placebo-controlled study.
  • One study arm will be dosed with anti-ST2 antibody intravenously every two weeks.
  • One study arm will be dosed with anti-ST2 antibody intravenously every four weeks.
  • Another arm will receive placebo. All subjects will continue to receive the standard of care therapy that they were receiving at study entry.
  • inflammation refers to an immunological defense against infection, marked by increases in regional blood flow, immigration of white blood cells, and release of chemical toxins. Inflammation is one way the body uses to protect itself from infection. Clinical hallmarks of inflammation include redness, heat, swelling, pain, and loss of function of a body part. Systemically, inflammation may produce fevers, joint and muscle pains, organ dysfunction, and malaise.
  • patient herein refers to a human patient.
  • COPD chronic obstructive pulmonary disease
  • COPD a progressive disease, i.e., the severity of the symptoms usually increases with the duration of the disease. In most cases of COPD, especially in advanced cases, a cure is impossible. Therapy rather aims at slowing the progress of the disease and relief of the symptoms. In most cases, the exposure to inhaled toxins, often tobacco smoke, causes a chronic bronchitis. Chronic bronchitis leads to increased secretion of mucus, swelling of the mucosa and bronchospasm.
  • COPD does not progress steadily, but rather shows periods of stable symptoms interrupted by periods of a sudden worsening of the disease, the acute exacerbations.
  • the COPD is accompanied by acute exacerbations.
  • COPD is defined as FEV1/FVC ratio of ⁇ 0.7 and bronchodilator response ⁇ 12%.
  • exacerbation refers to episodes of new or progressive increase in shortness of breath, cough (changes in sputum production and/or sputum quality and/or cough frequency and/or increased dyspnea), wheezing, chest tightness, nocturnal awakenings ascribed to one of the symptoms above or a combination of these symptoms.
  • the severity of an exacerbation ranges from mild to life-threatening and can be evaluated based on both symptoms and lung function.
  • an exacerbation is a COPD exacerbation, which is an acute worsening of respiratory symptoms that may result in additional therapy (GOLD 2021).
  • acute exacerbation refers to COPD exacerbations triggered by bacterial or viral infection of the airways or by environmental pollutants. Inflammation is increased during acute exacerbations. An acute exacerbation of COPD typically lasts for several days. Airway inflammation is increased during the exacerbation resulting in increased hyperinflation, reduced expiratory air flow and worsening of gas transfer.
  • Moderate exacerbation refers to COPD exacerbations requiring treatment with corticosteroids and/or antibiotics.
  • severe exacerbation refers to COPD exacerbations requiring hospitalization or that lead to death.
  • FEV1 refers to the volume of air exhaled in the first second of forced exhalation of air expellec from the lungs, starting from a position of maximum inspiration and with the subject making maximum effort. It is a measure of airway obstruction.
  • FVC force vital capacity
  • LAA long-acting beta-2 agonist, which agonist includes, for example, salmeterol, formoterol, bambuterol, albuterol, indacaterol, arforaioterol and cienbuterol.
  • LAMA long-acting muscarinic antagonist, which agonists include, for example, tiotropium.
  • LABA/LAMA combinations include but are not limited to: olodaterol tiotropium (Boehringer Ingeiheim's) and indacaterol glycopyrronium (Novartis).
  • an “intravenous” or “iv” dose, administration, or formulation of a drug is one which is administered via a vein, e.g., by infusion.
  • a “subcutaneous” or “sc” dose, administration, or formulation of a drug is one which is administered under the skin, e.g., via a pre-filled syringe, auto-injector, or other device.
  • a “fixed dose” of a drug refers to a dose that is administered without regard to the patient's weight.
  • a fixed dose of an anti-ST2 antibody provided herein is 476 mg, 700 mg, 490 mg, 350 mg, or 280 mg dose.
  • clinical status refers to a patient's health condition. Examples include that the patient is improving or getting worse. In some embodiments, clinical status is based on an ordinal scale of clinical status. In some embodiments, clinical status is not based on whether or not the patient has a fever.
  • PRO refers to instrument(s) completed to assess the treatment benefit and patient experience of Ab2.
  • the PRO includes SGRQ-C, mMRC, CAT, and/or EXACT.
  • SGRQ-C St. George's Respiratory Questionnaire-COPD
  • SGRQ-C St. George's Respiratory Questionnaire-COPD
  • SGRQ-C a self-report questionnaire designed to measure the impact of COPD on health and well-being through the patient's perception of COPD-related experiences (Meguro et al. 2007).
  • the SGRQ-C consists of 40 questions within 3 domains: symptoms (7 items), activity (13 items), and impacts (20 items). Each response has a unique, empirically derived weight. A total score is also produced. Lower scores of the SGRQ-C indicate better health-related quality of life.
  • the SGRQ-C has no specific recall period, with the exception of one item that assesses the frequency of chest trouble attacks during the past year.
  • the SGRQ-C takes approximately 10 minutes to complete.
  • mMRC Modified Medical Research Council Dyspnea Scale
  • COPD Assessment Test refers to a validated PRO that measures the impact of COPD on health status.
  • the CAT is an 8-item questionnaire that includes items related to cough, phlegm, chest tightness, breathlessness ascending hills/stairs, activity limitation at home, confidence leaving home, sleep, and energy.
  • the CAT uses a 6-point ordinal scale, ranging from 0 (no impairment) to 5 (maximum impairment), with a score range of 0-40 and higher scores indicating a greater disease impact. There is no specified recall period (questions are answered in reference to daily life); the questionnaire takes 1-2 minutes to complete.
  • EXAcerbations of Chronic Pulmonary Disease Tool and Evaluating Respiratory Symptoms in COPD or “EXACT” Questionnaire and the term “Evaluating Respiratory Symptoms in COPD” or “E-RS:COPD” Subset refer to a daily eDiary that assesses COPD exacerbations (Leidy et al. 2010).
  • the 14-item questionnaire contains four domains: breathlessness (5 items), cough and sputum (3 items), chest symptoms (3 items), and additional attributes (3 items), which includes tiredness/weakness, sleep disturbance, and fear/worry.
  • the EXACT has a recall period of “today”.
  • the subset E-RS:COPD is composed of the breathlessness, cough and sputum, and chest symptoms domains of the EXACT (11 total items) and, as such, it specifically assesses COPD symptoms (Leidy et al. 2014).
  • An E-RS:COPD total score is derived based on the three domains.
  • the daily eDiary entry including the EXACT plus a short-acting rescue medication question regarding rescue inhaler use, takes approximately 5 minutes to complete. Patients are asked to complete the diary every evening before going to bed.
  • an “ordinal scale” refers to a scale used to quantify outcomes which are non-dimensional. They can include an outcome at a single point in time or can examine change which has occurred between two points in time. In some embodiments, the two points of time are “Day 1” (when first dose of the ST2 antagonist is administered) compared with a later Day when the patient is evaluated and, optionally, at at a later Day when the patient is further evaluated. Ordinal scales include various “categories” which each evaluate patent status or outcome. In some embodiments, the ordinal scale is a “6-point ordinal scale”.
  • standard of care or “SOC” refers to treatments or drugs commonly used to treat patients with COPD including one of the following combinations of optimized, stable maintnenance therapy:
  • each nucleotide sequence is referred to as a “polymorphic variant” or a “nucleic acid variant.”
  • Each possible variant in the DNA sequence is referred to as an “allele.”
  • the polymorphic variant represented in a majority of samples from a population is referred to as a “prevalent allele,” or “major allele,” and the polymorpohic variant that is less prevalent in the population is referred to as an “uncommon allele” or “minor allele.”
  • human ST2 is a receptor also known as interleukin 1 receptor like 1 (IL1RL1).
  • ST2 is expressed on inflammatory cells including mast cells, basophils, innate lymphoid cells, T lymphocytes, and macrophages, and its ligand, IL33, is expressed at high levels in epithelial cells of mucosal tissues, particularly the lung, and acts as an ‘alarmin,’ being released upon inflammatory cell death, infection, or injury, to initiate innate immune responses.
  • Naturally occurring human ST2 variants are known and included in this definition.
  • Human ST2 amino acid sequence information has been disclosed, see for example, UniProtKB/Swiss-Prot Q01638.4.
  • Human IL-33 amino acid sequence has been disclosed, see for example, UniProtKB/Swiss-Prot: 095760.1.
  • a “native sequence” protein herein refers to a protein comprising the amino acid sequence of a protein found in nature, including naturally occurring variants of the protein.
  • the term as used herein includes the protein as isolated from a natural source thereof or as recombinantly produced.
  • Chimeric antibodies of interest herein include “primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey, such as baboon, rhesus or cynomolgus monkey) and human constant region sequences (U.S. Pat. No. 5,693,780).
  • a non-human primate e.g. Old World Monkey, such as baboon, rhesus or cynomolgus monkey
  • human constant region sequences U.S. Pat. No. 5,693,780
  • “Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • donor antibody such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
  • a “human antibody” herein is one comprising an amino acid sequence structure that corresponds with the amino acid sequence structure of an antibody obtainable from a human B-cell, and includes antigen-binding fragments of human antibodies.
  • Such antibodies can be identified or made by a variety of techniques, including, but not limited to: production by transgenic animals (e.g., mice) that are capable, upon immunization, of producing human antibodies in the absence of endogenous immunoglobulin production (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci.
  • the antibody herein may be a “glycosylation variant” such that any carbohydrate attached to the Fc region, if present, is altered.
  • a glycoslation variant such that any carbohydrate attached to the Fc region, if present, is altered.
  • antibodies with a mature carbohydrate structure that lacks fucose attached to an Fc region of the antibody are described in US Pat Appl No US 2003/0157108 (Presta, L.). See also US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).
  • Antibodies with a bisecting N-acetylglucosamine (GlcNAc) in the carbohydrate attached to an Fc region of the antibody are referenced in WO 2003/011878, Jean-Mairet et al. and U.S. Pat. No.
  • hypervariable region when used herein refers to the amino acid residues of an antibody that are responsible for antigen binding.
  • the hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” (e.g. as determined by Kabat: residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35 (H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD.
  • CDR complementarity determining region
  • a “full length antibody” is one which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH2 and CH3.
  • the constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variants thereof.
  • the full length antibody has one or more effector functions.
  • Antibody effector functions refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), etc.
  • full length antibodies can be assigned to different “classes”. There are five major classes of full length antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses” (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2.
  • the heavy-chain constant domains that correspond to the different classes of antibodies are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • recombinant antibody refers to an antibody (e.g. a chimeric, humanized, or human antibody or antigen-binding fragment thereof) that is expressed by a recombinant host cell comprising nucleic acid encoding the antibody.
  • host cells for producing recombinant antibodies include: (1) mammalian cells, for example, Chinese Hamster Ovary (CHO), COS, myeloma cells (including Y0 and NS0 cells), baby hamster kidney (BHK), Hela and Vero cells; (2) insect cells, for example, sf9, sf21 and Tn5; (3) plant cells, for example plants belonging to the genus Nicotiana (e.g.
  • Nicotiana tabacum (4) yeast cells, for example, those belonging to the genus Saccharomyces (e.g. Saccharomyces cerevisiae ) or the genus Aspergillus (e.g. Aspergillus niger ); (5) bacterial cells, for example Escherichia coli cells or Bacillus subtilis cells, etc.
  • yeast cells for example, those belonging to the genus Saccharomyces (e.g. Saccharomyces cerevisiae ) or the genus Aspergillus (e.g. Aspergillus niger );
  • bacterial cells for example Escherichia coli cells or Bacillus subtilis cells, etc.
  • binding affinity for antigen is of Kd value of 10 ⁇ 9 mol/l or lower (e.g. 10 ⁇ 10 mol/l), preferably with a Kd value of 10 ⁇ 10 mol/l or lower (e.g. 10 ⁇ 12 mol/l).
  • the binding affinity is determined with a standard binding assay, such as surface plasmon resonance technique (BIACORE®).
  • an “effective amount” or “therapeutically effective amount” of an agent, e.g., ST2 antagonist or a pharmaceutical formulation thereof refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • the expression “effective amount” in some embodiments refers to an amount of the ST2 antagonist that is effective for treating or preventing COPD.
  • an effective amount is 476 mg of an ST2 antagonist.
  • an effective amount is 476 mg SC every 2 weeks.
  • an effective amount is 476 SC every 4 weeks.
  • an effective amount is 490 mg SC every 4 weeks.
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of the active ingredient or ingredients to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile.
  • the formulation is for intravenous (iv) administration.
  • the formulation is for subcutaneous (sc) administration.
  • a “liquid formulation” or “aqueous formulation” according to the invention denotes a formulation which is liquid at a temperature of at least about 2 to about 8° C.
  • lyophilized formulation denotes a formulation which is dried by freezing the formulation and subsequently subliming the ice from the frozen content by any freeze-drying methods known in the art, for example commercially available freeze-drying devices.
  • Such formulations can be reconstituted in a suitable diluent, such as water, sterile water for injection, saline solution etc., to form a reconstituted liquid formulation suitable for administration to a subject.
  • a “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications, other therapeutic products to be combined with the packaged product, and/or warnings concerning the use of such therapeutic products, etc.
  • An “elevated” level of a biomarker refers to an amount of that biomarker in the patient that is above the upper limit of normal (ULN).
  • ST2 antagonists contemplated herein include antagonists that bind to ST2 or its ligand, IL-33.
  • the ST2 antagonist is an antibody.
  • the ST2 antagonist is an antibody that binds ST2.
  • the ST2 antagonist blocks the IL-33/ST2 receptor complex.
  • the ST2 antagonist blocks IL-33-mediated ST2 signaling.
  • Antibodies that bind ST2 include the human anti-ST2 antibodies described in WO 2013/173761 A2, which is incorporated by reference herein in its entirety for any purpose. Nonlimiting such antibodies include Ab2, Ab5, and Ab7, the sequences for which are provided in the Table of Certain Sequences herein.
  • the CDRs are determined according to Kabat. In some embodiments, the CDRs are determined according to IMGT.
  • amino acid sequences of the heavy chain complementarity determining regions H-CDR1, H-CDR2, H-CDR3, and the light chain complementarity determining regions L-CDR1, L-CDR2, and L-CDR3 of anti-ST2 antibody Ab2 are shown in SEQ ID NOs: 35, 36, 37, 38, 39, and 40, respectively, for example, as determined by IMGT.
  • the amino acid sequences of the heavy chain and light chain of anti-ST2 antibody Ab5 are shown in SEQ ID NOs: 19 (or SEQ ID NO: 33, which lacks the C-terminal lysine) and SEQ ID NO: 20, respectively.
  • the amino acid sequences of the heavy chain variable domain and light chain variable domain of anti-ST2 antibody Ab5 are shown in SEQ ID NOs: 17 and 18, respectively.
  • the amino acid sequences of the heavy chain complementarity determining regions H-CDR1, H-CDR2, H-CDR3, and the light chain complementarity determining regions L-CDR1, L-CDR2, and L-CDR3 of anti-ST2 antibody Ab5 are shown in SEQ ID NOs: 11, 12, 13, 14, 15, and 16, respectively.
  • the amino acid sequences of the heavy chain and light chain of anti-ST2 antibody Ab7 are shown in SEQ ID NOs: 29 (or SEQ ID NO: 34, which lacks the C-terminal lysine) and SEQ ID NO: 30, respectively.
  • the amino acid sequences of the heavy chain variable domain and light chain variable domain of anti-ST2 antibody Ab7 are shown in SEQ ID NOs: 27 and 28, respectively.
  • the amino acid sequences of the heavy chain complementarity determining regions H-CDR1, H-CDR2, H-CDR3, and the light chain complementarity determining regions L-CDR1, L-CDR2, and L-CDR3 of anti-ST2 antibody Ab7 are shown in SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively.
  • the ST2 antagonist is Ab2.
  • the amino acid sequence of the Ab2 light chain is as follows (SEQ ID NO: 10):
  • DIQMTQSPSS LSASVGDRVT ITCQASQDIS NYLNWYQQKP GKAPKLLIYD 50 ASNLETGVPS RESGSGSGTD FTFTISSLQP EDIATYYCQQ DDNFPLTEGG 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSEN RGEC. 214
  • the amino acid sequence of the Ab2 heavy chain is as follows (SEQ ID NO: 9):
  • the ST2 antagonist is a monoclonal antibody that binds IL-33.
  • the methods and articles of manufacture of the present invention use, or incorporate, an antibody that binds to human ST2.
  • ST2 antigen to be used for production of, or screening for, antibodies may be, e.g., a soluble form of ST2 or a portion thereof (e.g. the extracellular domain), containing the desired epitope.
  • cells expressing ST2 at their cell surface can be used to generate, or screen for, antibodies.
  • Other forms of ST2 useful for generating antibodies will be apparent to those skilled in the art.
  • the antibody is an antibody fragment, various such fragments being disclosed above.
  • the antibody is a chimeric, humanized, or human antibody or antigen-binding fragment thereof.
  • the antibody is a humanized full-length antibody.
  • ELISA enzyme linked immunosorbent assay
  • the anti-ST2 antibody is neutralizes IL-33 activity, e.g. by inhibiting binding of IL-33 to ST2.
  • An exemplary method for evaluating such inhibition is disclosed in WO 2013/173761 A2, for example.
  • the ability of the antibody to compete with IL-33 to ST2 is evaluated.
  • a plate is coated with ST2 (e.g. recombinant ST2 or sST2), a sample comprising the anti-ST2 antibody with labeled IL-33 is added, and the ability of the antibody to block binding of the labeled IL-33 to ST2 is measured.
  • the ability of an anti-ST2 antibody to inhibit the IL-33-mediated association of ST2 with coreceptor AcP is determined. See WO 2013/173761 A2.
  • Non-limiting examples of anti-ST2 antibodies herein include Ab2, Ab5, and Ab7 (WO 2013/173761 A2).
  • the antibody herein is preferably recombinantly produced in a host cell transformed with nucleic acid sequences encoding its heavy and light chains (e.g. where the host cell has been transformed by one or more vectors with the nucleic acid therein).
  • the preferred host cell is a mammalian cell, most preferably a Chinese Hamster Ovary (CHO) cells.
  • Therapeutic formulations of the antibodies used in accordance with the present invention are prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers ( Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
  • the formulation herein may also contain more than one active compound as necessary, preferably those with complementary activities that do not adversely affect each other.
  • the type and effective amounts of such medicaments depend, for example, on the amount of antibody present in the formulation, and clinical parameters of the subjects. Exemplary such medicaments are discussed below.
  • the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-( ⁇ )-3-hydroxybutyric acid.
  • LUPRON DEPOTTM injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • poly-D-( ⁇ )-3-hydroxybutyric acid poly-D-( ⁇ )-3-hydroxybutyric acid.
  • the invention provides a method of treating chronic obstructive pulmonary disease (COPD) in a patient comprising administering 476 mg of an ST2 antagonist to the patient on Day 1 of a treatment period.
  • COPD chronic obstructive pulmonary disease
  • a method of reducing the frequency of moderate to severe exacerbations in a patient having COPD comprising administering 476 mg of an ST2 antagonist to the patient on Day 1 of a treatment period.
  • additional drugs as set forth herein are generally used in the same dosages and with administration routes as used hereinbefore or about from 1 to 99% of the heretofore-employed dosages. If such additional drugs are used at all, preferably, they are used in lower amounts than if the first medicament were not present, especially in subsequent dosings beyond the initial dosing with the first medicament, so as to eliminate or reduce side effects caused thereby.
  • Anti-ST2 is presented as sterile, clear, and colourless to slightly yellow liquid. Each sterile vial is filled with a 1 mL deliverable volume of 70 mg/mL. It is formulated with 15 mM sodium acetate, 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 20, pH 5.2.
  • Placebo for Anti-ST2 (MSTT1041A) is formulated with 10 mM sodium acetate, 9.0% (w/v) sucrose, 0.004% (w/v) polysorbate 20, pH 5.2, and is supplied in an identical vial configuration.
  • the primary outcome is frequency of moderate to severe exacerbation (defined as requiring treatment with systemic corticosteroids and/or antibiotics in the community or hospital or hospitalisation) in 48 weeks. Astegolimab treatment demonstrated numerical reductions in COPD exacerbations.
  • FIG. 1 shows the distribution of the number of moderate-to-severe exacerbations among subjects by treatment arm.
  • 3 A- 3 B demonstrate the annualized exacerbation rate per baseline blood eosinophil sub-groups, having, respectively, baseline blood eosinophil counts of ⁇ 170 eosinophils/ ⁇ L and >170 eosinophils/ ⁇ L, or ⁇ 300 eosinophils/ ⁇ L and ⁇ 300 eosinophils/ ⁇ L.
  • FIG. 3 A the sub-group having baseline blood eosinophil ⁇ 170 eosinophils/ ⁇ L showed an AERR of 31% and the sub-group having baseline blood eosinophil >170 eosinophils/ ⁇ L showed an AERR of 17%.
  • FIG. 3 B shows an AERR of 37% for the subgroup having a baseline blood eosinophil count of ⁇ 300 eosinophils/ ⁇ L.
  • FIGS. 5 A- 5 B show the SGRQ total scores based on the baseline blood eosinophil sub-groups for, respectively, eosinophil group having low ( ⁇ ) or high (>) 170 eosinophils/ ⁇ L ( FIG. 5 A ) or ⁇ or ⁇ 300 eosinophils/ ⁇ L ( FIG. 5 B ).
  • FIG. 6 shows the change from baseline in post-BD FEV1 during the 48 weeks for all-comers.
  • FIGS. 7 A- 7 B show the changes in post-BD FEV1 for baseline blood eosinophil sub-groups having, respectively, low ( ⁇ ) or high (>) 170 eosinophils/ ⁇ L ( FIG. 7 A ) or ⁇ or ⁇ 300 eosinophils/ ⁇ L ( FIG. 7 B ).
  • FIGS. 8 A- 8 B show the change from baseline in blood eosinophil level over 48 weeks.
  • the median blood eosinophil count was 170 cells/ ⁇ L.
  • the geometric mean ratio for the blood eosinophil count compared to placebo from baseline to week 48 was 0.61 (0.50 to 0.73; p ⁇ 0.001).
  • FIG. 9 shows the change from baseline in % sputum eosinophil count over 48 weeks.
  • FIG. 10 A- 10 C shows certain adverse events for treatment compared to placebo.
  • FIG. 10 A provides the frequency of certain adverse events (AEs)
  • FIG. 10 B- 10 C provides number of adverse events or number of serious adverse events (SAEs) per patient.
  • SAEs serious adverse events
  • Example 2 A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Astegolimab in Patients with Chronic Obstructive Pulmonary Disease
  • the primary efficacy objective for this study is to evaluate the efficacy of astegolimab compared with placebo on the basis of the following endpoint:
  • the secondary efficacy objective for this study is to evaluate the efficacy of astegolimab compared with placebo on the basis of the following endpoints:
  • the further efficacy objective for this study is to evaluate the efficacy of astegolimab compared with placebo on the basis of the following endpoints:
  • the safety objective for this study is to evaluate the safety of astegolimab compared with placebo on the basis of the following endpoints:
  • PK pharmacokinetic
  • IL-33 is considered an “alarmin” or a damage-associated molecular pattern molecule that is constitutively expressed on epithelial cells and released upon cell injury or stress from exposure to such exogenous stimuli as allergens, toxins, or infections.
  • IL-33 is a member of the IL-1 family of cytokines (Sims and Smith 2010) with potential as a target in the treatment of asthma, COPD, and atopic dermatitis.
  • IL-33 High levels of IL-33 are found in stromal cells, particularly at barrier surfaces such as the lung and gastrointestinal tract. Within the lung, IL-33 is detected in multiple cell types, including epithelial cells, endothelial cells, and fibroblasts (Liew et al. 2016). IL-33 bioavailability is tightly regulated, and under homeostatic conditions, this protein is sequestered in the nuclei of these cells. Cellular damage caused by injury, mechanical stress, or death leads to the release of bioactive IL-33 into circulation, where it initiates and propagates innate and adaptive immune responses.
  • the receptor for IL-33, ST2 is expressed on multiple cell types implicated in pulmonary inflammation and disease, including mast cells, eosinophils, basophils, innate lymphoid cells, T lymphocytes, macrophages, and endothelial cells.
  • IL-33 is also linked to the function of type-2 innate lymphocytes that accumulate in the lung and promote T helper type 2 (Th2) cell inflammation, even in the absence of antigen stimulation (Scanlon and McKenzie 2012). In some settings, IL-33 will also promote type 1 responses, such as interferon (IFN)- ⁇ production from natural killer (NK) cells or NK T cells. As such, IL-33 may be involved in multiple inflammatory pathways implicated in COPD.
  • IFN interferon
  • NK T cells natural killer cells
  • IL-33 activates these various immune cells through its receptor ST2, also known as Il-1 receptor-like 1 (IL-1RL1) (Nabe 2014).
  • ST2 also known as Il-1 receptor-like 1
  • IL-1RL1 Il-1 receptor-like 1
  • Intracellular signaling induced by IL-33 promotes expression of inflammatory genes.
  • a secreted soluble form of ST2 (sST2) arises from alternative splicing, is elevated in settings of inflammation, and acts as a decoy to bind and inhibit released IL-33 (Hayakawa et al. 2007).
  • IL-33 is highly inflammatory in pulmonary tissue and is capable of triggering local inflammation that can lead to airway hyperresponsiveness (AHR) and mucus production, important components of exacerbations.
  • AHR airway hyperresponsiveness
  • Airway administration of IL-33 in mice leads to an infiltration of inflammatory cells in bronchoalveolar lavage fluid, including eosinophils and neutrophils, as well as elevated interleukin-5, interleukin-13, eotaxin, and thymus and activation-regulated chemokine (also known as TARC/CCL17) (Louten et al. 2011).
  • TARC/CCL17 activation-regulated chemokine
  • IL-33 release can trigger acute exacerbations and/or disease progression in asthma, COPD, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome.
  • IL-33 activity is elevated following viral infections, and inhibition of this pathway reduces virus-induced exacerbations in rodent models of asthma and COPD (Werder et al. 2018; Ravanetti et al. 2019).
  • ST2- or IL-33-deficient mice exposed to cigarette smoke have decreased inflammatory responses in response to subsequent respiratory viral infections, without compromising anti-viral host defense (Kearley et al. 2015).
  • the absence of the IL-33 pathway significantly reduced viral-induced leukocyte migration into the lung, inflammatory cytokine expression, and subsequent pulmonary pathology. For these reasons, inhibiting ST2 is hypothesized to confer clinical benefit to patients with COPD by limiting excessive inflammatory sequelae.
  • patients Following a screening period of at least 7 days to up to 4 weeks, patients will be randomized in a 1:1:1 ratio to one of three treatment arms to receive blinded treatment with either astegolimab or placebo. Randomization will be stratified by smoking status at screening (former smoker vs. current smoker) and region.
  • the first dose of study drug (astegolimab or placebo) will be administered on Day 1; treatment will continue through at least Week 50, followed by a 12-week safety follow-up period.
  • the treatment regimens for each arm are as follows:
  • Alpha-diversity is a measure of ecological diversity and can be employed for estimating microbiome diversity in a particular sample using high dimensional microbiome assays, e.g. sequencing.
  • Sputum 16s rRNA v4 amplicon sequencing was employed for microbiome analysis and negative binomial regression including study stratification factors and baseline ⁇ -diversity dichotomized at the observed median as model terms to estimate treatment effect and annualized exacerbation rate. Model estimates are represented as lsmeans [5% confidence intervals].
  • Shannon-Weaver method was used to calculate the ⁇ -diversity index (Hurlbert, S. H. Ecology 1971).
  • the pretreatment lung microbial ⁇ -diversity is prognostic for increased COPD exacerbations and treatment benefit from anti-ST2 therapy.

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